Process for the preparation of alpha&#39; chloroketones

ABSTRACT

The present invention relates to a process for the preparation of α′ chloroketones, such as 4-phenyl-3-t-butyloxy-carbonylamino)-2-keto-1-chlorobutane by reacting certain aryl amino acid esters, e.g. N-(2-t-butoxycarbonyl)-L-phenylalanine-4-nitrophenyl ester, with a sulfur ylide compound to form the corresponding keto ylide compound which is then treated with a source of chloride and an organic acid.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. ProvisionalApplication Ser. No. 60/225,711 filed Aug. 16, 2000.

FIELD OF THE INVENTION

[0002] The present invention relates to a novel process for thepreparation of α′-N-acyl-α′-chloroketones. The α′-chloroketones producedin accordance with the process of the invention are precursors ofhydroxyethylamine isostere sub-units present in many moleculestherapeutically useful as inhibitors of angiotensin converting enzyme,renin and HIV-protease.

BACKGROUND OF THE INVENTION

[0003] A process for preparing α-haloketones is described by König andMezger in Chem. Ber., Vol. 98, pages 3733-3747, 1965. The disclosedprocess involves the reaction of dimethyl-oxo-sulfoniummethylide withisocyanates and ketenes to form β-keto-sulfoniummethylides. On page3738, in Table 3, there is disclosed treatment of theβ-keto-sulfoniummethylides with hydrochloric acid or bromine to formα-chloroketone or α,α-dibromoketone.

[0004] Degraw and Cory, Tetrahedron Letters, No. 20, pages 2501-2501,1968, disclose the preparation of α-acetoxy and α-halomethylketones fromacyloxosulfonium ylides by the action of acids. This paper also teachesthat the selective preparation of α-halo and α-acetoxymethyl ketones bythe reaction of halogen acids or organic acids with α-diazoketones iswell known. Given that the diazoketones are usually obtained by thereaction of diazomethane with the appropriate acid chloride, the methodtaught by this paper is not considered attractive for large-scaleapplications.

[0005] Powers and Wilcox, J. Am. Chem. Soc., 92, page 1782, 1970describe a classical method for the preparation of α-chloroketonesinvolving the conversion of an N-acyl-α-amino acid to a α-diazoketoneand subsequent acidolysis with HX. The use of diazomethane in thismethod makes it impractical for large-scale operations and also imposessafety considerations.

[0006] Kowalski et al., J. Org. Chem., Vol. 50, 5140, 1985 and J. Org.Chem., Vol. 57, 7194, 1992, describe homologation of esters toα-bromoketones utilizing the reagent system CH₂Br₂/LDA/n-BuLi.

[0007] Baldwin et al., Synlett, pages 51-53, 1993 describe a processwhereby a nucleophilic ring compound, an activated monocyclic β-lactam,is opened by reaction with trimethylsulfoxonium ylide, lithiatedsulfones and cuprates to form a variety of functionalized γ-keto-α-aminoacids that are useful intermediates for the synthesis of naturalproducts.

[0008] Chen and Cheng, Tetrahedron Letters, Vol. 38, No. 18, pages3175-3178, 1997, describes the development of reactions for thepreparation of α-chloroketones and proposes a practical process for thepreparation of α′-chloroketones of N-carbamate-protected α-amino acidsby reaction of lithium diisopropylamide and chloroiodomethane withBOC-L-phenylalanine ethyl ester.

[0009] This process, however, is disadvantageous in that there is formedthe high-boiling, toxic by-product chlorodiiodomethane.

SUMMARY OF THE INVENTION

[0010] The present invention is directed to an improved process for thepreparation of α-N-acyl-α′-chloroketones by the action of a sulfur ylideon aryl esters to generate a keto ylide that is in turn treated with asource of chloride and an organic acid. The present invention is furtherdirected to an improved process for the preparation of correspondingepoxide compounds that are intermediates in the synthesis of animportant HIV protease inhibitor.

DETAILED DESCRIPTION OF THE INVENTION

[0011] The process of the present invention provides an advantageoussynthesis for the α-N-acyl-α′-chloroketones represented by the formula

[0012] wherein R is selected from the group consisting of alkyl,substituted alkyl, aryl and substituted aryl and R₁ is a protectinggroup for the amino function.

[0013] The compounds represented by formula I are irreversible enzymeinhibitors and are also useful as intermediates in the synthesis ofmolecules that are inhibitors of ACE, renin and HIV proteases. Suchcompounds and their use are disclosed, for example, in U.S. Pat. No.5,849,911, the disclosure of which is incorporated herein by reference.

[0014] As utilized herein, the following terms have the definitionsgiven below.

[0015] The term “alkyl” refers to optionally substituted straight- orbranched-chain saturated hydrocarbon groups having from 1 to 7 carbonatoms, preferably from 1 to 4 carbon atoms. The expression “lower alkyl”refers to optionally substituted alkyl groups having from 1 to 4 carbonatoms.

[0016] The term “substituted alkyl” refers to an alkyl group substitutedby, for example, one to four substituents, such as, halo,trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkyoxy,heterocylooxy, oxo, alkanoyl, aryl, aryloxy, aralkyl, alkanoyloxy,amino, alkylamino, arylamino, aralkylamino, cycloalkylamino,heterocycloamino and disubstituted amino. The definitions given hereinfor alkyl and substituted alkyl apply as well to the alkyl portion ofalkoxy groups.

[0017] The term “aryl” refers to monocyclic or bicyclic aromatichydrocarbon groups having from 6 to 12 carbon atoms in the ring portion,for example, phenyl, naphthyl, biphenyl and diphenyl groups, each ofwhich may be substituted.

[0018] The term “aralkyl” refers to an aryl group bonded to a largerentity through an alkyl group, for example, a benzyl radical.

[0019] The term “substituted aryl” refers to an aryl group substitutedby, for example, one to four substituents such as alkyl; substitutedalkyl, halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy,cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino,dialkylamino, aralkylamino, cycloalkylamino, heterocycloamino,alkanoylamino, thiol, alkylthio, cycloalkylthio, heterocyclothio,ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl,alkylthiono, arylthiono, alkysulfonyl, sulfonamido, aryloxy and thelike. The substituent may be further substituted by one or more membersselected from the group consisting of halo, hydroxy, alkyl, alkoxy,aryl, substituted alkyl, substituted aryl and aralkyl.

[0020] The term “protecting group on the amino function” refers to anart-recognized group of moieties that can be attached to an amino groupto keep it from being involved in reactions taking place elsewhere onthe moiety to which it is attached. Preferred among such groups ist-butoxycarbonyl (BOC), but art-recognized amino function protectinggroups, generally alkoxycarbonyl or aryloxycarbonyl groups, such asbenzyloxycarbonyl, can be used as well.

[0021] The starting materials for the process of preparingα-chloroketones in accordance with the present invention are aryl estersrepresented by the formula

[0022] wherein R and R₁ are as defined above and R₂ is hydrogen or nitroand may be substituted in the ortho or para position on the phenyl ring.The compounds represented by formula II are commercially available orcan be prepared by techniques well known to those of ordinary skill inthe art. The protecting group on the amino function is preferablyt-butoxycarbonyl (BOC), but can also be other art-recognized aminofunction protecting groups as discussed above.

[0023] In accordance with the process of the present invention, thestarting material represented by formula II above is treated with asulfur ylide, i.e. a compound containing a function represented by theformula

[0024] to produce an intermediate keto ylide compound represented by theformula

[0025] wherein R and R₁ are as defined above and R₃ and R₄ are selectedfrom the group consisting of alkyl, substituted alkyl and aryl. Thesulfur ylide reagent is conveniently prepared from a sulfoxonium salt byreaction with a suitable base in an organic solvent. Suitablesulfoxonium compounds include trialkyl sulfoxonium halides, such astrimethylsuloxonium iodide. Preferable bases include, for example,sodium hydride, potassium tert, butoxide and potassium tert, amylate,with the latter being particularly preferred. The reaction is carriedout in an organic solvent such as dimethylformamide, tetrahydrofuran or,preferably, toluene with mild heating, i.e. at a temperature of fromabout 60° C. to about 80° C., preferably about 70° C.

[0026] Once the sulfur ylide reagent is formed, it is reacted with thestarting material represented by formula II above, optionally in thepresence of a co-solvent. As an example of the use of a mixed solventreaction medium, the reaction of the trialkylsulfoxonium compound andbase is carried out in toluene as described, the resulting solution iscooled to about 0° C., and then added to a solution of the startingmaterial in tetrahydrofuran to form the keto ylide intermediate compoundrepresented by formula III above.

[0027] The keto ylide compound represented by formula III is thenconverted to the subject α-N-acyl-α′-chloroketones by reaction with asource of chloride, preferably a basic source of chloride, mostpreferably lithium chloride, and an organic acid, for example,methanesulfonic acid. The treatment with the source of chloride iscarried out in an organic solvent, such as tetrahydrofuran, toluene or,preferably, acetonitrile. The reaction is initiated at low temperature,i.e. from about 0° C. to about 5° C. As the reaction proceeds, however,the temperature is raised to about 65° C. Reaction of the keto yliderepresented by formula III above with a quaternary chloride, such astetrabutylammonium chloride, yields a mixture of products resulting fromcompetitive dealkylation.

[0028] The α-N-acyl-α′-chloroketones represented by formula I above, inaddition to their own activity as irreversible enzyme inhibitors, areimportant intermediates in the synthesis of molecules that areinhibitors of ACE, renin and HIV proteases. The activity of suchmolecules against HIV proteases makes them very valuable in thetreatment of retroviral infections such as AIDS. Specifically, theα-N-acyl-α′-chloroketones represented by formula I are converted byreduction either chemically or enzymatically to an intermediaterepresented by the formula IV that is, in turn treated with a suitablebase to convert it to the corresponding epoxide represented by formula Vas shown below

[0029] The epoxide compounds represented by formula V are intermediatesthat can be converted to the important HIV protease inhibitor2,5,6,10,13-pentaazaretetradecanedioic acid,3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6{[4-(2-pyridinyl)phenyl]methyl}-dimethylester (3S,8S,9S,12S) as disclosed in U.S. Pat. No. 5,849,911, thedisclosure of which is incorporated herein by reference. The synthesisof the compounds represented by formula V above beginning with thecompound represented by formula II is an improvement over syntheticroutes known heretofore.

[0030] It is understood that various other embodiments and modificationsin the practice of the invention will be apparent to, and can be readilymade by, those of ordinary skill in the art without departing from thescope and spirit of the invention as described above. Accordingly, it isnot intended that the scope of the claims appended hereto be limited tothe exact description set forth above, but rather that the claims beconstrued as encompassing all of the features of patentable novelty thatreside in the present invention, including all the features andembodiments that would be treated as equivalents thereof by thoseskilled in the relevant art. The invention is further described withreference to the following experimental work.

EXAMPLE 1

[0031] Preparation of(3S)-2-oxo-3-(t-butyloxycarbonylamino)-4-phenylbutylidedimethylsulfoxonium

[0032] A one liter flask equipped with a large stir bar, a refluxcondenser and an argon inlet was charged with trimethylsulfoxoniumiodide (35.3 g, 160.5 mmol) and tetrahydrofuran (200 mL). There was thenadded with stirring 88 mL of a 25 wt % solution of potassium t-amylatein toluene (176.0 mmol) and the reaction was stirred at 70° C. for twohours to afford the corresponding ylide which was reacted in solutionwithout isolation. The reaction mixture was cooled to 1° C. and asolution of N-(2-t-butoxycarbonyl)-L-phenylalanine-4-nitrophenyl ester(20.0 g, 51.8 mmol) in 80 mL of tetrahydrofuran was added via cannulaover 15 minutes so that the internal temperature remained between 1° and5° C. The reaction was stirred at this temperature for about fiveminutes and then was allowed to warm to ambient temperature over 30minutes. The reaction mixture was stirred at ambient temperature for afurther 30 minutes. HPLC analysis of an aliquot of the reaction mixturediluted with 1 mL of acetonitrile and 5 drops of water showed completeconsumption of the N-t-butoxycarbonyl-L-phenylalanine-4-nitrophenylester.

[0033] The reaction mixture was quenched with 100 mL of water andstirred for 15 minutes after which it was concentrated under vacuum toremove organic solvents. The concentrated mixture was diluted with afurther 550 mL of water and extracted with one 200 mL portion and two100 mL portions of dichloromethane. The combined extracts were washedwith two 200 mL portions of water, dried over magnesium sulfate andconcentrated under vacuum. The residual solvents were removed under highvacuum for 30 minutes to obtain the product as a light yellow solid(17.4 g., 99%) which was carried on to Example 2 without furtherpurification.

EXAMPLE 2

[0034] Preparation of (S)-[N-(1-benzyl-2-oxo-3-chloro)propyl]carbamicacid t-butyl ester

[0035] A one liter flask equipped with a large stir bar, a refluxcondenser and an argon inlet was charged with(3S)-2-oxo-3-(t-butyloxycarbonylamino)-4-phenylbutylidedimethylsulfoxonium (17.0 g, 50.0 mmol) and 250 mL of tetrahydrofuran.The mixture was cooled to 1° C. and lithium chloride (2.55 g, 60.1 mmol)was added in a single portion (the internal temperature of the reactionmixture rose to 2° C). Methanesulfonic acid (3.6 mL, 55.1 mmol) wasadded over five minutes so that the internal temperature of the mixtureremained between 1° C. and 3° C., after which the mixture was stirred at65° C. for four hours. The reaction mixture stirred as a very thickslurry for the first thirty minutes of this period. HPLC revealedcomplete consumption of the starting material and formation of(S)-[N-(1-benzyl-2-oxo-3-chloro)propyl]carbamic acid t-butyl ester. Thereaction was allowed to cool to ambient and concentrated under vacuum toa solid/oil mixture. The mixture was taken up in 170 mL of ethylacetate, washed with 80 mL of half-saturated aqueous sodium bicarbonateand 80 mL of saturated aqueous sodium chloride, dried over magnesiumsulfate, filtered and concentrated under vacuum. The residual solventswere removed under high vacuum overnight to obtain(S)-[N-(1-benzyl-2-oxo-3-chloro)propyl]carbamic acid t-butyl ester as acrude product, 14.5 g, 97%, as a light yellow solid. A 500 mL flask witha large stir bar and a reflux condenser was charged with crude product,14.25 g, and 210 mL of hexanes. The mixture was stirred at reflux and 10ml of methyl t-butyl ether was added to dissolve the solid. The solutionwas allowed to cool to ambient temperature over one hour. The solutionbecame cloudy and then turned into a very thick slurry which was stirredfor two hours. The product was collected by filtration and washed with25 mL of hexanes followed by 35 mL of hexanes. The product was air-driedfor one hour to afford 11.9 g of(S)-[N-(1-benzyl-2-oxo-3-chloro)propyl]carbamic acid t-butyl ester, 81%overall yield, as an off-white solid.

EXAMPLE 3

[0036] Preparation of(S,S)-[N-(1-benzyl-2-hydroxy-3-chloro)propyl]carbamic acid t-butylester.

[0037] A solution of (S)-[N-(1-benzyl-2-oxo-3-chloro)propyl]carbamicacid t-butyl ester prepared in Example 2 (5 g, 16.8 mmol) in 84 mL oftetrahydrofuran and 9 mL of water is treated with sodium borohydride(1.59 g, 42 mmol) at 0° C. The temperature is maintained with stirringfor 45 minutes, after which the reaction mixture is concentrated todryness. The residue is stirred at 0° C. with a mixture of 150 mL ofethyl acetate and 25 mL of water while saturated potassium bisulfitesolution is carefully added until the pH of the mixture reaches about pH1.5. The resulting mixture is diluted with 350 mL of ethyl acetate andthe layers separated. The organic layer is washed with water and brine,dried over magnesium sulfate and concentrated to a white solid. Thematerial is recrystallized from hot ethyl acetate to afford(S,S)-[N-(1-benzyl-2-hydroxy-3-chloro)propyl]carbamic acid t-butyl ester(2.57 g, 50%). The minor amount of the (S,R) diastereomer is isolatedfrom the mother liquor.

EXAMPLE 4

[0038] Preparation of 1-(1′(R)-oxiranyl)-2-(phenylethyl)carbamic acidt-butyl ester.

[0039] A 10 mL flame-dried flask equipped with a stir bar and an argoninlet was charged with(S,S)-[N-(1-benzyl-2-hydroxy-3-chloro)propyl]carbamic acid t-butyl esteras prepared in Example 3 (200 mg, 0.67 mmol), isopropanol (3.6 mL) andtetrahydrofuran (1 mL). The solution was cooled to 16° C. and potassiumtert-butoxide (79 mg. 0.67 mmol) was added in one portion. The reactionwas stirred at approximately 17° C. for 30 minutes. Acetic acid (3drops) was added thereto and the mixture was concentrated to asolid/liquid mixture. The mixture was taken up in methyl, tert. butylether (10 mL) and washed with water (5 mL), saturated sodium hydrogencarbonate solution (1.5 mL), half-saturated sodium hydrogen carbonatesolution (1.5 mL) and saturated sodium hydrogen carbonate solution (1.5mL). The resultant organic layer was dried with magnesium sulfate,filtered and concentrated to afford1-(1′(R)-oxiranyl)-2-(phenylethyl)carbamic acid t-butyl ester (170 mg.,96%) as a light-yellow oil which solidified at room temperature.

We claim:
 1. A process for the preparation of α-N-acyl-α′-chloroketonesrepresented by the formula

wherein R is selected from the group consisting of alkyl, substitutedalkyl, aryl and substituted aryl and R₁ is a protecting group for theamino function comprising reacting aryl esters represented by theformula

wherein R and R₁ are as defined above and R₂ is hydrogen or nitro andmay be substituted in the ortho or para position on the phenyl ring witha compound containing a function represented by the formula

wherein R₃ and R₄ are selected from the group consisting of alkyl,substituted alkyl and aryl, to produce an intermediate keto ylidecompound represented by the formula

and treating said compound represented by formula III with a source ofchloride and an organic acid.
 2. A process in accordance with claim 1,wherein R is phenyl and R₁ is t-butoxycarbonyl.
 3. A process inaccordance with claim 1, wherein R₂ is nitro and is substituted in thepara position on the phenyl ring.
 4. A process in accordance with claim1, where R₃ and R₄ are each methyl.
 5. A process in accordance withclaim 1, additionally including the step of forming said sulfur ylidecompound by the reaction of a sulfoxonium compound with a base in anorganic solvent.
 6. A process in accordance with claim 5, wherein saidsulfoxonium compound is a trialkyl sulfoxonium halide and said base ispotassium tert-amylate.
 7. A process in accordance with claim 1, whereinthe reaction of said compound represented by formula II with said sulfurylide compound is carried out in an organic solvent at a temperature offrom about 60° C. to about 80° C.
 8. A process in accordance with claim6, where said solvent is at least one member selected from the groupconsisting of dimethylformamide, tetrahydrofluran and toluene.
 9. Aprocess in accordance with claim 1, wherein said source of chloride islithium chloride.
 10. A process in accordance with claim 1, wherein saidorganic acid is methanesulfonic acid.
 11. A process in accordance withclaim 1, wherein the reaction of said keto ylide compound represented byformula III with the source of chloride and the organic acid isinitiated at a temperature of from about 0° C. to about 5° C. in anorganic solvent.
 12. A process in accordance with claim 11, wherein saidsolvent is tetrahydrofuran.
 13. A process of preparing an epoxy compoundrepresented by the formula

wherein R is selected from the group consisting of alkyl, substitutedalkyl, aryl and substituted aryl and R₁ is a protecting group for theamino function, comprising reacting an aryl ester represented by theformula

wherein R and R₁ are as defined above and R₂ is hydrogen or nitro andmay be substituted in the ortho or para position on the phenyl ring witha compound containing a function represented by the formula

wherein R₃ and R₄ are selected from the group consisting of alkyl,substituted alkyl and aryl to produce an intermediate keto ylidecompound represented by the formula

wherein R, R₁, R₃ and R₄ are as defined above, treating said compoundrepresented by formula III with a source of chloride and an organic acidto form a 1-substituted-2-amino-3-oxo-4-chloro butane compoundrepresented by the formula

wherein R and R₁ are as defined above, reducing said compound to form a1-chloro-2-hydroxy-3-amino-4-substituted butane compound represented bythe formula

wherein R and R₁ are as defined above and reacting said hydroxy compoundwith a base to form said epoxy compound.
 14. A process in accordancewith claim 13, wherein R is phenyl and R₁ is t-butyloxycarbonyl.
 15. Aprocess in accordance with claim 13 wherein R₂ is nitro and issubstituted in the para position on the phenyl ring.
 16. A process inaccordance with claim 13, where R₃ and R₄ are each methyl.
 17. A processin accordance with claim 13, additionally including the step of formingsaid sulfur ylide compound by the reaction of a sulfoxonium compoundwith a base in an organic solvent.